Thianthrene and phenoxathiine s-oximides

ABSTRACT

The present invention is concerned with novel tricyclic sulphoximides and with the preparation thereof. This family of compounds has been found to possess antihistominic, antitussive, antiinflammatory, sedative, and diuretic properties.

This is a division, of application Ser. No. 496,600 now U.S. Pat. No.3,978,052 patented, Aug. 31, 1976 filed Aug. 12, 1974.

The cyclic sulphoximides have not been hitherto investigated to anygreat extent. For this reason, very little is known about thepharmacological effectiveness of these compounds. We have found howeverthe aromatic compounds of this type to be of interest because of theirpotential physiological effectiveness.

More particularly, we have found that the new compounds of this clinicalfamily posses an antitussive, antihistaminic, antiphlogistic, sedativeand diuretic effectiveness.

We have now found that the tricyclic sulphoximide family of the generalformula: ##STR1## wherein X is a valency bond, a sulphur or oxygen atom,an unsubstituted or substituted imino group, or a carbonyl group, alower alkylene radical which can be interrupted by an oxygen or sulphuratom or by a carbonyl group or by an unsubstituted or substituted iminogroup; R is an optionally N-alkylated or N-acylated amino-alkyl,aminoalkycarbonyl, alkoxycarbonyl, aminocarbonyl or aminothiocarbonylradical posses these valuable pharmacological properties. Thepharmaceutically acceptable salts of these compounds of course alsopossess these properties.

Lower alkylene radicals according to the present invention arepreferably methylene and ethylene radicals and the oxa, thia and azaanalogues thereof which, as substituents, can include lower hydrocarbonradical. Thus X can be, for example, an ethylidene, propylidene,isobutylidene, propylene, 1,2 -butylene or 1,2 -isobutyl-idene radical,one ring carbon atom of which can be replaced by an oxygen or sulphuratom or by a carbonyl group or by an unsubstituted or substituted iminogroup. By a substituted imino group, there is to be understood an iminogroup which is substituted by an alkyl radical containing up to 4 carbonatoms, for example, by a methyl, ethyl, isopropyl, n-butyl or isobutylradical, or by an acyl radical containing up to 4 carbon atoms, forexample, an acetyl, propionyl or butyryl radical. The above-givengeneral formula I thus includes the following tricyclic systems:dibenzothiophene-S-oximide, thiaxanthene-S-oximide,thiaxanthone-S-oximide, phenoxathiine-S-oximide, thianthrene-S-oximide,phenothiazine-S-oximide, dibenzo[b,f] thiepine-S-oximide, 10, 11-dihydrodibenzo[b,f]thiepine-S-oximide, 10, 11-dihydrobenzo[(b,f]thiepine-10 -one-S-oximide, dibenzo[ b,e]-1,4-oxa-thiepine-S-oximide, dibenzo[ b,e]dithiepine-S-oximide, 10, 11-dihydrodibenzo[ b,f]-1,4 -thiazepine-S-oximide and dibenzo[ b,f]-1,4-thiazepine-S-oximide.

The aminoalkyl radical R can be, for example, a tertiary amino group,which can be open-chained or cyclic, attached through a lower alkyleneradical to the nitrogen atom of the sulphoximide group. Preferredradicals are those of the general formula: ##STR2## wherein n is 1, 2, 3or 4 and R₁ and R₂, which can be the same or different, are saturated orunsaturated aliphatic hydrocarbon radicals containing up to 7 carbonatoms; R₁ and R₂ together may also represent an alkylene chaincontaining 4 to 6 carbon atoms.

The aminoalkylcarbonyl radical R can be a tertiary amine radical, whichis open-chained or cyclic, the nitrogen atom of which is connected,through a lower alkyl-carbonyl radical containing 2 to 4 carbon atoms,to the nitrogen atom of the sulphoximine group. Preferred radicals arethose of the general formula: ##STR3## wherein R₁ and R₂ have the samemeanings as above and n is 1, 2, or 3.

The alkoxycarbonyl radical R can be, for example, one of the generalformula:

    --CO--O--R.sub.3                                           IV

wherein R₃ is a alkyl radical containing up to 4 carbon atoms and ispreferably an ethyl radical.

The aminocarbonyl or aminothiocarbonyl radical R can be, for example, onof the general formula: ##STR4## wherein X' is an oxygen or sulphur atomand R₄ and R₅ , which can be the same or different, are hydrogen atomsor saturated or unsaturated aliphatic hydrocarbon radicals containing upto 6 carbon atoms.

Furthermore, if the radical R contains a primary or secondary aminogroup, this group can be acylated by alkanoyl radicals containing 2 to 4carbon atoms, for example, acetyl or propinoyl radicals, or by sulphonylradicals, for example benzene-sulphonyl or tosyl radicals.

The radicals R₁ and R₂ are preferably methyl, ethyl, propyl, butyl,hexyl, vinyl, propenyl, allyl or butenyl radicals; or R₁ and R₂ ,together with the nitrogen atom to which they are attached preferablyrepresent a pyrrolidino, piperidino or perhydroazepino radical.

The compounds of general formula I can be prepared from new tricyclicsulphoximides of the general formula: ##STR5## wherein X has the samemeaning as above, or from an alkali metal or alkaline earth metal saltthereof by the following process: when R is to be an aminoalkyl radical,by reaction with an appropriate alkyl halide, especially with a compoundof the general formula: ##STR6## wherein m, R₁ and R₂ have the samemeanings as above and Hal is a halogen atom, preferably a chlorine orbromine atom; when R is to be an aminoalkylcarbonyl radical, by reactionwith a reactive derivative of an appropriate acid, especially with areactive derivative of an acid of the general formula; ##STR7## whereinn, X', R₁ and R₂ have the same meanings as above; when R is to be analkoxycarbonyl radical, by reaction with a halocarbonic acid ester ofthe general formula:

METHOD C

    Hal--CO--O--R.sub.3                                        IX

wherein Hal and R₃ have the same meanings as above; and when R is to bean aminocarbonyl or aminothiocarbonyl radical, by reaction with acorresponding isocyanate or isothiocyanate or with a free acid of thegeneral formula:

METHOD D

    X'=C=N--R.sub.4                                            X

wherein R₄ and X' have the same meanings as above, or with a reactivederivative of the corresponding carbamic acid of the general formula:##STR8## wherein X' , R₄ and R₅ have the same meanings as above.

As reactive derivatives of acids used according to method "B", there canbe used, for example, acid halides, acid anhydrides or acidimidazolides. This reaction depends upon the reactivity of the startingmaterials employed. In most cases, the variant described hereinafter ispreferred. As reactive carbamic acid derivatives used according tomethod "D" , there can be used, for example, a carbamic acid in the formof a halide, especially of a chloride.

Reaction "B" can also be carried out by first reacting a compound (VI)with a dihalide of the general formula: ##STR9## wherein Hal, X' and nhave the same meanings as above, followed by reaction with an amine ofthe general formula:

    R.sub.l --NH-- R.sub.2                                     XIII

wherein R₁ and R₂ have the same meanings as above.

The compounds of general formula (VI) used as starting materials arealso novel and encompassed by this invention. They can be prepared, forexample, by reacting a sulphimide of the general formula: ##STR10##wherein X has the same meaning as above, or a salt thereof with anoxidation agent, or by reacting a suplhoxide of the general formula:##STR11## wherein X has the same meanings as above, either with asulphonyl-azide of the general formula:

    Ar--SO.sub.2 --N.sub.3                                     XVI

wherein Ar is an unsubstituted or substituted phenyl radical, with theaddition of copper powder as catalyst, in methanol; or withO-mesitylenesulphonyl-hydroxylamine in an inert solvent; whereafter, ifdesired, any N-arylsulphonyl radicals present and any N-acyl radicals onthe substituent X can be split off hyrdolytically, and the free basesconverted into salts by reaction with inorganic or organic acids.

As oxidation agents for the sulphimides of general formula (XIV), therecan be used, sodium periodate, hydrogen peroxide, lead tetraacetate orpotassium permanganate. The reaction can be carried out in anappropriate solvent or solvent mixture, depending upon the nature of theoxidation agent used. Examples of such solvents include glacial aceticacid, water, pyridine, chloroform, dichloromethane, dichloroethanedioxan, acetone or a lower alcohol. The reaction is preferably carriedout at ambient temperature with the use of a molar amount or of anexcess of oxidation agent.

The course of the oxidation reaction "A"is surprising and was not tohave been foreseen. The oxidation of N-unsubstituted sulphimides ispreviously only described for dimethyl sulphimide (see Chem. Ber., 95,855/1962 ), whereas the oxidation of aromatic substituted sulphimides tothe corresponding sulphoximides has hitherto not been described.Surprisingly, however, the compounds of general formula (XIV) can beoxidised without difficulty to compounds of general formula (VI). Inthis case, the desired result is obtained not only with the use ofpotassium permanganate, as described in the literature for examples ofthe aliphatic series, but also with much weaker oxidation agents (seeJ.A.C.S., 94, 208/1972; Tetrahedron, 27, 341/1971 ).

The compounds of general formulae (VI) and (XIV) form crystallineaddition salts not only with inorganic acids but also with organicacids, for example, hydrochloric acid, hydrobromic acid, hydrofluoricacid, sulphuric acid, orthophosphoric acid, metaphosphoric acid, nitricacid, chloric acid, perchloric acid, sulphonic acids, oxalic acids,acetic acid, formic acid, succinic acid, citric acid, fumaric acid,lactic acid and the like.

The sulphimides of general formula (XIV) and the salts thereof are alsonew. They can be prepared, for example, by reacting sulphides of thegeneral formula: ##STR12## wherein X has the same meaning as above, withmesitylene-sulphonyl-hydroxylamine in an inert solvent. The initiallyformed mesitylene-sulphonates can, if desired, be converted in knownmanner into the bases (XIV). Salts with inorganic or organic acids can,if desired, be prepared in the usual manner from these bases.

As inert solvent, there can be used a chlorinated hydrocarbon, such asdichloromethane or chloroform. The mesitylene-sulphonyl-hydroxylaminecan be added in solid form or as a solution and the reaction can becarried out at a temperature of between about 0° C. and 30° C. over thecourse of 2 to 48 hours. The mesitylene-sulphonates of the compounds(XIV) usually precipitate out and can be separated off directly. In somecases, however, it is necessary to promote the precipitation by theaddition of ether or of petroleum ether.

The compounds of general formula (XV) are either known or can beprepared in known manner from the corresponding sulphides. The reactionwith the compounds of general formula (XVI) preferably takes place in alower alcohol, for example methanol, ethanol or isopropanol, at theboiling point of the solvent. The reaction time is about 6 to 24 hours.

The aryl radical of the compounds (XVI) can be substituted by halogenatoms or by lower alkyl radicals, p-toluene-sulphonyl azide,p-chlorobenzenesulphonyl azide or p-bromobenzene-sulphonyl azidepreferably being used.

The copper powder used as catalyst should be as finely divided aspossible. It is preferably used in 0.2 to 0.5 times the amount in gramsof the amount of azide used.

The reaction of the compounds (XV) withO-mesitylene-sulphonyl-hydroxylamine is carried out in a manneranalogous to that described for compounds of general formula (XVI).

If the imino group of the sulphoximide group is, after the reaction ofthe compounds (XV), substituted by an arylsulphonyl radical, this can besplit off by hydrolysis with a strong acid, preferably concentratedsulphuric acid. The saponification requires temperatures of between 0and 100° C. and, depending upon the reactivity, a reaction time of from5 minutes to 24 hours. The reaction mixture is subsequently poured intowater, rendered alkaline with a base, for example with an aqueoussolution of sodium or potassium hydroxide or of ammonia and thenextracted with an appropriate solvent, for example dichloromethane,chloroform or the like. The free base (VI) obtained after distilling offthe solvent can then, if desired, be recrystallized and converted into asalt by reaction with an appropriate acid, preferably with hydrogenchloride.

The splitting off of any N-acyl radicals which may be present can becarried out even under quite mild conditions, for example, by hydrolysisin dilute hydrochloric acid or by means of an alcoholic solution ofpotassium hydroxide.

The following examples are given for the purpose of illustrating theformation of the novel family of compounds encompassed by generalformula VI:

EXAMPLE I Thianthrene-S-oximide

Thianthrene-S-imide mesitylene sulphonate is prepared in the followingmanner:

A solution of 90 g. thianthrene in 1.6 liters methylene chloride ismixed at ambient temperature with 100 g. mesitylene sulphonylhydroxylamine. The reaction mixture is left to stand for 48 hours andthe thianthrene-S-imide mesitylene sulphonate formed is thanprecipitated out with ether. The yield is 79 % of theory. Afterrecrystallization from ethyl acetate/diisopropyl ether, the compound hasa melting point of 156° C.

The free base, obtained from alkaline solution, can be recrystallizedfrom ethyl acetate and has a melting point of 153° C.

30 g. thianthrene-S-imide mesitylene sulphonate are dissolved in 580 ml.glacial acetic acid and mixed at ambient temperature with a solution of45 g. sodium periodate in 300 ml. water. The reaction mixture is stirredfor 24 hours at ambient temperature, then poured on to ice, renderedalkaline with an aqueous solution of sodium hydroxide and subsequentlyextracted with methylene chloride. After stripping off the solvent, theresidue obtained is recrystallized from ethyl acetate.Thianthrene-S-oximide is thus obtained in the form of colorless crystalswhich contain 0.75 mol water of crystallization. The yield is 55 % oftheory and the product melts at 193° C.

EXAMPLE 2 10 -Methyl-phenothiazine-S-oximide

10 -methyl-phenothiazine-S-imide is prepared in the following manner:

To a solution of 18.1 g. 10 -methyl-phenothiazine in 250 ml. methylenechloride, there is added dropwise, while stirring and cooling, asolution of 18.3 g. mesitylene sulphonyl hydroxylamine in 50 ml.methylene chloride. After a short time, the 10-methyl-phenothiazine-S-imide mesitylene sulphonate precipitates out. Itis filtered off with suction and recrystallized from isopropanol.whereafter it has a melting point of 169°-170° C.; yield 83 % of theory.

The free base obtained from alkaline solution can be recrystallized frommethanol and has a melting point of 114°-115° C.

12.6 g. 10 -methyl-phenothiazine-S-imide are dissolved in 110 ml.glacial acetic acid and mixed dropwise with a solution of 23.4 g. sodiumperiodate in 100 cc. water. The reaction mixture is then stirred for 16hours at ambient temperature. After evaporation in a vacuum, the residueobtained is mixed with water, rendered alkaline with an aqueous solutionof potassium hydroxide, extracted with methylene chloride and theextract evaporated to dryness. The residue obtained is recrystallizedfrom isopropanol. There is obtained 10 -methyl-phenothiazine-S-oximidein a yield of 42% of theory; m.p. 174°-175° C.

EXAMPLE 3 10 -Acetyl-phenothiazine-S-oximide

10 -acetyl-phenothiazine-S-imide mesitylene sulphonate is prepared asfollows:

120.6 g. 10 -acetyl-phenothiazine in 1.3 liters methylene chloride aremixed with a solution of 107.6 g. mesitylene sulphonyl hydroxylamine ina little methylene chloride and stirred for 18 hours at ambienttemperature. The reaction mixture is then cooled to 0° C. and theprecipitate formed is filtered off with suction. There is obtained 10-acetyl-phenothiazine-S-imide mesitylene sulphonate in a yield of 55 %of theory; m.p. 189° C.

The free base obtained from alkaline solution is recrystallized fromethyl acetate and then melts at 139°-140° C.

118.5 g. 10 -acetyl-phenothiazine-S-imide mesitylene sulphonate in 400ml. glacial acetic acid are oxidised with 110 g. sodium periodate in 200ml. water over the course of 20 hours at ambient temperature. Afterevaporation of the reaction mixture in a vacuum, the residue is mixedwith water, rendered alkaline with an aqueous solution of sodiumhydroxide and extracted with methylene chloride. The extract isevaporated and the residue obtained is recrystallized from ethylacetate. There is obtained 10 -acetyl-phenothiazine-S-oximide in a yieldof 45 % of theory; m.p. 153°-154° C.

EXAMPLE 4 Phenothiazine-S-oximide

1.3 g. of the 10 -acetyl-phenothiazine-S-oximide prepared in the mannerdescribed in Example 3 are heated for 1 hour at 50° C. with 0.56 g.potassium hydroxide in 50 ml. ethanol. Thereafter, the reaction mixtureis mixed with water and the precipitate obtained is filtered off withsuction. There is thus obtained phenothiazine-S-oximide in a yield of 77of theory. After recrystallization from methanol, the compound has amelting point of 279°-280° C.

EXAMPLE 5 Dibenzothiophene-S-oximide VARIANT A

A solution of 19 g. dibenzothiophene-S-oxide in 1 liter methanol ismixed, under a protective atmosphere of nitrogen, with 20 g.p-toluene-sulphonyl azide and 6 g. copper powder. The reaction mixtureis heated under reflux for a total time of 20 hours, whereby, after 4, 8and 12 hours, 2 g. copper powder and 5 g. of the tosyl azide are added.Thereafter, the reaction mixture is filtered while still hot to separateoff the precipitate, which is thoroughly washed with hot acetone. Thefiltrate is concentrated to about one third of its initial volume, thereaction product thereby separating out in the form of a crystallineprecipitate. This is filtered off with suction and recrystallized fromethanol. There is obtainedN-(p-toluene-sulphonyl)-dibenzothiophene-S-oximide in a yield of 62 % oftheory; m.p. 175° C.

7 g. of the tosylate thus obtained are heated in 5 ml. concentratedsulphuric acid for 5 minutes on a steam-bath and thereafter poured intoice water. The reaction mixture is rendered alkaline, while cooling,extracted with methylene chloride and the organic phase dried and thenevaporated. The residue obtained is recrystallized from methanol. Thereis obtained pure dibenzothiophene-S-oximide; m.p. 171° C. Thesaponification step takes place with a yield of 85 % of theory.

VARIANT B

74 g. dibenzothiophene-S-oxide are dissolved in 1 liter methylenechloride and mixed, while cooling with ice, with a solution of 86.2 g.mesitylene-sulphonyl-hydroxylamine in a little methylene chloride. Thereaction mixture is stirred for 20 hours at ambient temperature and theprecipitate formed then filtered off with suction. Afterrecrystallization thereof from methanol, dibenzothiophene-S-oximidemesitylene-sulphonate it obtained in a yield of 40 % of theory; m.p.196°-197° C. This salt is dissolved in methanol and mixed with a molaramount of sodium methylate, water is subsequently added thereto and theprecipitate formed is filtered off with suction and recrystallized frommethanol. There is thus obtained pure dibenzothiophene-S-oximide; m.p.171° C.

EXAMPLE 6 Thioxanthene-S-oximide

16 g. thioxanthene-S-oxide, 20 g. p-tosyl-azide and 6 g. copper powderare reacted and worked up in a manner analogous to that described inExample 5, Variant A. The residue of theN-p-toluene-sulphonyl-thioxanthene-S-oximide (m.p. 220° C.; yield 48 %of theory) obtained as intermediate can be recrystallized fromacetonitrile. After saponification with concentrated sulphuric acid andrecrystallization from isopropanol, there is obtained purethioxanthene-S-oximide; m.p. 174° C. The yield from the saponificationstep is 79 % of theory.

EXAMPLE 7 Thioxanthone-S-oximide

10.7 g. thioxanthone-S-oxide in 600 ml. methanol are reacted in 600 ml.methanol, in the manner described in Example 5, Variant A, with 11 g. 4-chlorobenzene-sulphonyl azide and 4.5 copper powder and thenappropriately worked up. The residue obtained of the intermediate N-(4-chlorobenzene-sulphonyl)-thioxanthone-S-oximide (m.p. 192° C,; yield 60% of theory) can be recrystallized from acetonitrile. Aftersaponification with concentrated sulphuric acid and recrystallization ofthe product from isopropanol, pure thioxanthone-S-oximide is obtainedwhich melts at 168°-169° C. The saponification step proceeds with ayield of 83 % of theory.

EXAMPLE 8 Phenoxathiine-S-oximide VARIANT A

10.8 g. phenoxathiine-S-oxide are reacted with 10 g. tosyl azide and 4.5g. copper powder in 350 ml. methanol in the manner described in Example5, Variant A. After 1.5 and 3 hours, a further 5 g. tosyl azide and 4.5g. copper powder are added. The reaction time is 6 hours. The residueobtained after working up is the intermediateN-(p-toluene-sulphonyl)-phenoxathiine-S-oximide which, afterrecrystallization from acetonitrile, melts at 170°-171° C. The yield is60 % of theory.

After saponification with concentrated sulphuric acid andrecrystallization from benzene/diisopropyl ether, there is obtained purephenoxathiine-S-oximide, which melts at 108-109° C. The saponificationstep gives a yield of 80° of theory.

VARIANT B

20.8 g. phenoxathiine-S-imide mesitylene sulphonate are dissolved in 300ml. glacial acetic acid and oxidised with 21.3 g. sodium periodate in300 ml. water. The reaction mixture is stirred for a further 24 hours atambient temperature, then poured on to ice, rendered alkaline withaqueous sodium hydroxide solution and extracted with methylene chloride.After stripping off the solvent in a vacuum, the residue obtained isrecrystallized from benzene/diisopropyl ether. Purephenoxathiine-S-oximide is obtained in a yield of 86 % of theory; m.p.108°-109° C.

The phenoxathiine-S-imide-mesitylene sulphonate is prepared in thefollowing manner:

5 g. phenoxathiine are stirred for 48 hours at ambient temperature with6 g. mesitylene sulphonyl hydroxylamine in 50 ml. methylene chloride.The reaction mixture is subsequently mixed with a large amount of etherand the precipitate obtained is filtered off with suction. Afterrecrystallization thereof from ethyl acetate/isopropanol, there isobtained phenoxathiine-S-imide mesitylene sulphonate in a yield of 57 %of theory; m.p. 165° C.

EXAMPLE 9 N-chloroacetyl-phenoxathiine-S-oximide

11.5 g. phenoxathiine-S-oximide and 7.6 g. triethylamine are dissolvedin 150 cc. chloroform. While stirring and cooling, there is addeddropwise a solution of 7.9 g. chloroacetyl chloride in 50 cc.chloroform. After having stirred the reaction mixture for 30 minutes atambient temperature, it is mixed with water, acidified with dilutehydrochloric acid and the phases separated. The chloroform phase iswashed with water, dried and evaporated. The crystalline residue isrecrystallized from isopropanol, whereafter it melts at 137°-138° C.

Using the product of the above examples, the products of general formulaI can be prepared.

Process "A" is, most simply, carried out be dissolving the startingmaterials of general formula (VI) in a dry solvent, for example,benzene, toluene a xylene, tetrahydrofuran, dioxan or dimethylsulphoxide, and, by the addition of a molar amount of sodium, potassiumor sodium hydride at a temperature between about 20° C. and 100° C.,converting them into the corresponding sulphoximide alkali metal salts.To the reaction mixture there is subsequently added a compound ofgeneral formula (VII) and the reaction mixture allowed to react at 50°to 150° C. for 30 minutes to 10 hours.

Methods "B" and "C" can be carried out by reacting the starting materialof general formula (VI) in an appropriate solvent, for examplechloroform, dichloromethane, benzene, toluene, a xylene, dioxan,tetrahydrofuran or acetone, with the addition of a hydrohalic acidacceptor, for example, triethylamine, pyridine or potassium carbonate,with a molar amount or an excess of a carboxylic acid chloride,preferably a chloride of an acid of general formula (VIII), or of ahalocarbonic acid ester of general formula (XI), at ambient temperaturefor 1 to 20 hours. Carbamic acid halides are reacted in an analogousmanner according to method "D".

The reaction according to "D" can take place in a solvent, for example,benzene, toluene, a xylene, dioxan, tetrahydrofuran or acetone, or in anexcess of the isocyanate or isothiocyanate used of general formula (X)at a temperature of 20° to 140° C. for a period of 1 to 24 hours. If thefree isocyanic or isothiocyanic acid is used, the reaction can becarried out with the addition of an inorganic or organic acid,preferably of acetic or trifluoroacetic acid.

If the compounds (I) possess a free basic amino group, they can beconverted into pharmacologically compatible salts in the conventionalmanner, for example, by neutralization of the free base withpharmacologically compatible inorganic or organic acids, for example,hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid,acetic acid, lactic acid, citric acid, malic acid, salicylic acid,malonic acid, maleic acid or succinic acid.

The following examples are given for the purpose of illustrating theformation of the novel family of compounds encompassed by generalformula I:

EXAMPLE 10 N-(2-Diethylaminoethyl)-dibenzothiophene-S-oximide

13.4 g. dibenzothiophene-S-oximide are dissolved in 700 cc. anhydroustoluene, mixed portionwise with 3 g. sodium hydride (as a 50 % oilsuspension) and heated to 80° C. for 15 minutes. The sodium salt of thesulphoximide precipitates out in the form of a voluminous precipitate.10 g. 2 -diethylaminoethyl chloride are added dropwise to thissuspension and the reaction mixture thereafter heated under reflux for 6hours. After cooling, the reaction mixture is poured into water and thetoluene phase separated off. This is washed with water, dried overanhydrous sodium sulphate and evaporated. The residue obtained isdissolved in ether and mixed with an ethereal solution of fumaric acid.The fumarate of N-(2 -diethylaminoethyl)-dibenzothiophene-S-oximideprecipitates out in the form of a colorless precipitate which isseparated off and recrystallized from isopropanol; m.p. 170° C.

In an analogous manner, there is obtained N-(2-piperidino-ethyl)-dibenzothiophene-S-oximide dibenzothiophene-S-oximidefrom dibenzothiophene-S-oximide and 2 -piperidinoethyl chloride. Theoxalate thereof has a melting point of 216° C., after recrystallizationfrom ethyl acetate.

EXAMPLE 11 N-(2 -Diethylaminoethyl)-phenoxathiine-S-oximide

A solution of 9.3 g. phenoxathiine-S-oximide in 400 cc. anhydrous dioxanis mixed portionwise with an equimolar amount of sodium hydride andbriefly heated to the boil, a voluminous precipitate of the sodium saltof the sulphoximide thereby being formed. 8 g. 2 -diethylaminoethylchloride is added dropwise to this suspension, followed by heating underreflux for 3 hours. Thereafter, the reaction mixture is evaporated in avacuum, the residue obtained is taken up in dichloromethane and theorganic phase is washed with water, dried over anhydrous sodium sulphateand evaporated. The residue is converted into the corresponding oxalatein the usual manner. There is obtained N-(2-diethylaminoethyl)-phenoxathiine-S-oximide oxalate which, afterrecrystallization from ethanol, melts at 163° C.

In an analogous manner, there is obtained N-(3-dimethylaminopropyl)-phenoxathiine-S-oximide dihydrochloride which,after recrystallization from ethyl acetate/isopropanol, melts at186°-188° C.

EXAMPLE 12 N-(2-Diethylaminoethyl)-thioxanthene-S-oximide

In a manner analogous to that described in Example 11, by the reactionof thioxanthene-S-oximide with 2 -diethylaminoethyl chloride, there isobtained N-(2 -diethylaminoethyl)-thioxanthene-S-oximide dihydrochloridewhich, after recrystallization from isopropanol/ethanol, melts at 198°C.

EXAMPLE 13 N-(2 -Diethylaminoethyl)-thianthrene-S-oximide

Diethylaminoethyl chloride is reacted with thianthrene-S-oximide in amanner analogous to that described in Example 11 . There is obtainedN-(2 -diethylaminoethyl)-thianthrene-S-oximide which, afterrecrystallization from diisopropyl ether, melts at 100° C.

EXAMPLE 14 N-(2 -Piperidinoethyl)-thioxanthone-S-oximide

Thioxanthone-S-oximide is reacted with 2 -piperidino-ethyl chloride in amanner analogous to that described in Example 11 . N-(2-piperidinoethyl)-thioxanthone-S-oximide hydrochloride is obtainedwhich, after recrystallization from isopropanol, melts at 200° C.

The following compound is obtained in an analogous manner: N-(3-dimethylaminopropyl)-thioxanthone-S-oximide hydrochloride which, afterrecrystallization from isopropanol/methanol melts at 199°-210° C.

EXAMPLE 15 10 -Methyl-phenothiazine-N-(2 -diethylaminoethyl)-S-oximide

In a manner analogous to that described in Example 11, by the reactionof 10 -methyl-phenothiazine-S-oximide with 2 -diethylaminoethylchloride, there is obtained10-methyl-phenothiazone-N-(2-diethylaminoethyl)-S-oximide which, afterrecrystallization from diisopropyl ether/ethyl acetate, melts at 82°-83°C.

EXAMPLE 16 10 -Acetyl-phenothiazine-N-(3 -dimethylaminopropyl-S-oximide-dimethylaminopropyl)-S-oximide

10 -acetyl-phenothiazine-S-oximide is reacted with 3-dimethylaminopropyl chloride in a manner analogous to that described inExample 11 . There is obtained 10 -acetyl-phenothiazine-N-(3-dimethylaminopropyl)-S-oximide which, after recrystallization fromethyl acetate, melts at 149°-150° C.

In an analogous manner, there is obtained 10 -acetyl-phenothiazine-N-(2-piperidinoethyl)-S-oximide which, after recrystallization from ethylacetate, melts at 140° C.

EXAMPLE 17 Phenothiazine-N-(2 -piperidinoethyl)-S-oximide

In a manner analogous to that described in Example 11,phenothiazine-S-oximide is reacted with 2 -piperidinoethyl chloride.Phenothiazine-N-(2-piperidinoethyl)-S-oximide dihydrochloride is thusobtained which, after recrystallization from methanol/ether, melts, withdecomposition, at 284° C.

EXAMPLE 18 N-(Diethylaminoacetyl)-phenoxathiine-S-oximide

A mixture of 14.8 g. N-chloroacetyl-phenoxathiine-S-oximide, 14.6 g.diethylamine and 250 cc. anhydrous ethanol is heated under reflux for 2hours. Thereafter, the reaction mixture is evaporated in a vacuum andthe residue is mixed with a dilute aqueous solution of sodium hydroxideand then extracted with chloroform. The extract is washed with water,dried over anhydrous sodium sulphate and evaporated. The crystallineresidue is recrystallized from isopropanol.N-(diethylaminoacetyl)-phenoxathiine-S-oximide is obtained which meltsat 112° C. The corresponding hydrochloride melts, with decomposition, at213° C.

EXAMPLE 19 10 -Methyl-phenothiazine-N-(3-diethylaminopropionyl)-S-oximide

10 -Methyl-phenothiazine-N-(3 -chloropropiony)-S-oximide is reacted withdiethylamine in a manner analogous to that described in Example 18 . 10-methyl-phenothiazine-N-(3 diethylaminopropionyl)-S-oximidehydrochloride is obtained which, after recrystallization fromisopropanol, melts at 197°-198° C.

The 10 -methyl-phenothiazine-N-(3 -chloropropionyl)-5 -oximide used isobtained by the reaction of 10 -methyl-phenothiazine-S-oximide with 3-chloropropionyl chloride. After crystallization from ethyl acetate itmelts at 156°-158° C.

EXAMPLE 20 10 -Acetyl-phenothiazine-N-(ethoxycarbonyl)-S-oximide

13 g. ethyl chloroformate are added dropwise to a solution of 13.6 g. 10-acetyl-phenothiazine-S-oximide and 5.1 g. triethylamine in 150 cc.chloroform and the reaction mixture thereafter heated under reflux for10 hours. After cooling, the chloroform phase is washed with water,dried over anhydrous sodium sulphate and evaporated. The residue isrecrystallized from chloroform/methanol. 10-Acetyl-phenothiazine-N-(ethoxycarbonyl)-S-oximide is obtained; m.p.187°-188° C.

EXAMPLE 21 N-carbamoyl-dibenzothiophene-S-oximide

12.9 g. dibenzothiophene-S-oximide are dissolved in 300 cc. 80 % aceticacid and mixed with a solution of 9.7 g. potassium cyanate in 20 cc.water. The solution is stirred for 2 hours at 80° C., a precipitatethereby being obtained. This is filtered off with suction, washed withwater and recrystallized from dimethyl formamide.N-Carbamoyl-dibenzothiophene-S-oximide is obtained; m.p. 266°-267° C.

EXAMPLE 22 N-(n-Butyl-carbamoyl)-dibenzothiophene-S-oximide

10.8 g. dibenzothiophene-S-oximide, together with 5.5 g. n-butylisocyanate, are heated under reflux for 20 hours in 250 cc. anhydroustoluene. Thereafter, the reaction mixture is evaporated in a vacuum andthe residue obtained is recrystallized from ethyl acetate.N-(n-Butyl-carbamoyl)-dibenzothiophene-S-oximide is obtained; m.p.121°-122° C.

The following compounds are obtained in an analogous manner by thereaction of the appropriate S-oximides with the appropriate isocyanatesor isothiocyanates:

N-(butyl-carbamoyl)-phenoxathiine-S-oximide; m.p. 139° C.(recrystallized from ethyl acetate);

N-(n-butyl-carbamoyl)-thianthrene-S-oximide; m.p. 146° C.(recrystallized from ethyl acetate);

10 -acetyl-phenothiazine-N-(cyclohexyl-carbamoyl)-S-oximide; m.p.221°-222° C. (recrystallized from chloroform/ether);

phenethiazine-N-(cyclohexyl-carbamoyl)-S-oximide; m.p. 251°-252° C.(recrystallized from ethanol);

10-methyl-phenothiazine-N-(allyl-thiocarbamoyl)-S-oximide; m.p.187°-188° C. (recrystallized from chloroform/ether); and

10-methyl-phenothiazine-N-(p-toluene-sulphonyl-carbamoyl)-S-oximide;m.p. 273°-274° C. (decomp.) (recrystallized from dimethylformamide/ethanol).

10-methyl-phenothiazine-S-oximide: ##STR13##

10-acetyl-phenothiazine-S-oximide: ##STR14##

Phenothiazine-S-oximide: ##STR15##

Dibenzothiophene-S-oximide: ##STR16##

Thioxanthene-S-oximide: ##STR17##

Thioxanthone-S-oximide: ##STR18##

Phenoxathiine-S-oximide: ##STR19##

Thianthrene-S-oximide: ##STR20##

The compounds of the present invention include those having thefollowing structural formula:

    ______________________________________                                         ##STR21##                                                                                               melting point                                      Example    X              (° C)                                        ______________________________________                                        1          S              193                                                 2          H.sub.3 CN<    174-175                                             3          H.sub.3 CCON<  153-154                                             4          HN<            279-280                                             5          --             171                                                 6          CH.sub.2       174                                                 7          CO             168-169                                             8          O              108-109                                             ______________________________________                                    

the compounds (I) and the salts thereof can be administered enterally orparenterally in admixture with solid or liquid pharmaceutical diluentsor carriers. As injection medium, there is preferably used water whichcontains the conventional additives for injection solutions, for examplestabilizing agents, solubilizing agents or buffers. Additives of thistype include, for example, tartrate and citrate buffers, ethanol,complex-forming agents, for example, ethylenediamine-tetraacetic acidand the non-toxic salts thereof and high molecular weight polymers, forexample liquid polyethylene oxide, for viscosity regulation. Solidcarrier materials include, for example, starch, lactose, mannitol,methylcellulose, talc, highly-dispersed silicic acids, high molecularweight fatty acids, for example stearic acid, gelatine, agar-agar,calcium phosphate, magnesium stearate, animal and vegetable fats andsolid high molecular weight polymers, for example, polyethylene glycols;compositions suitable for oral administration can, if desired, containflavoring and sweetening agents.

The dosage of the compounds according to the present invention dependsupon the nature and severity of the disease to be treated. The oralindividual dose is usually 20 to 200 mg., the intravenous individualdose is usually 1 to 20 mg. and the subcutaneous individual dose isusually 1 to 100 mg.

We claim:
 1. Tricyclic sulphoximide of the general formula: ##STR22##wherein X is oxygen, sulfur, or the pharmacologically compatible saltsthereof.
 2. The sulphoximide of claim 1 which is Thianthrene-S-oximide.3. The sulphoximide of claim
 1. which is Phenoxathline-S-oximide.